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上海士鋒生物關(guān)于免疫蛋白STIM1的雙重功能
最近更新時(shí)間：2013-6-21
提 供 商：上海士鋒生物科技有限公司資料大小：10.1KB
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過去人們普遍認(rèn)為離子通道的選擇性是固定不變的，并且通道的開放和離子選擇是兩個(gè)互不相關(guān)的過程。近期由美國西北大學(xué)范伯格醫(yī)學(xué)院分子藥理和生物化學(xué)助理教授Murali Prakriya領(lǐng)導(dǎo)的一個(gè)小組發(fā)現(xiàn)免疫反應(yīng)關(guān)鍵調(diào)控因子STIM1蛋白不僅具有開啟CRAC通道孔的功能，且對該通道的離子選擇性起決定作用。這對于推動(dòng)設(shè)計(jì)出靶向治療免疫疾病的藥物具有非常重要的價(jià)值。
鈣離子在免疫細(xì)胞的大量細(xì)胞功能中起關(guān)鍵性的作用，鈣離子持續(xù)地流入免疫細(xì)胞中可激活細(xì)胞內(nèi)的基因表達(dá)，促使細(xì)胞增殖。從而啟動(dòng)了免疫細(xì)胞的開關(guān)。而STIM1是免疫細(xì)胞中一種重要的內(nèi)質(zhì)網(wǎng)鈣離子感受器，在機(jī)體對抗病原體過程中，STIM1蛋白感受到細(xì)胞內(nèi)的鈣離子變化，發(fā)生積聚并易位到質(zhì)膜附近。積聚的STIM1蛋白隨后會激活Orai1，促使CRAC鈣通道孔開放，鈣離子內(nèi)流從而導(dǎo)致細(xì)胞激活。
在這篇文章中，西北大學(xué)范伯格醫(yī)學(xué)院的研究人員構(gòu)建了一個(gè)突變的CRAC通道從而使孔道在無STIM1協(xié)助的情況下也能得以開放。然而研究人員發(fā)現(xiàn)在缺乏STIM1的情況下，多種離子包括鈉離子和鉀離子均通過了開放的CRAC通道孔。而在恢復(fù)STIM1的功能后，CRAC通道重新恢復(fù)了對鈣離子的選擇性。研究人員還證實(shí)甚至在STIM1低水平的情況下，未突變的通道也會喪失正常的高度鈣離子選擇性，使得多種離子得以進(jìn)入細(xì)胞。這些結(jié)果表明STIM1事實(shí)上起著調(diào)控CRAC通道開放和選擇性的雙重功能。
此外，Prakriya研究小組還鑒別出了調(diào)控CRAC通道開關(guān)的閘門（gate）的位置。Prakriya說：“研究調(diào)控開關(guān)的通道孔的分子及結(jié)構(gòu)區(qū)域?qū)τ谕苿?dòng)設(shè)計(jì)出靶向CRAC通道治療免疫疾病的藥物具有非常重要的價(jià)值。”
CRAC通道和STIM1蛋白對于激活免疫系統(tǒng)起著至關(guān)重要的作用。新研究發(fā)現(xiàn)*扭轉(zhuǎn)了科學(xué)家們對于離子通道運(yùn)行機(jī)制的認(rèn)識。不僅揭示了CRAC通道運(yùn)行的新機(jī)制，并且揭示了編碼生物學(xué)信息的新途徑。這為開發(fā)出多種疾病例如自身免疫性疾病和變態(tài)反應(yīng)的治療新策略帶來了新希望。
Gated regulation of CRAC channel ion selectivity by STIM1
Two defining functional features of ion channels are ion selectivity and channel gating. Ion selectivity is generally considered an immutable property of the open channel structure, whereas gating involves transitions between open and closed channel states, typically without changes in ion selectivity1. In store-operated Ca2+ release-activated Ca2+ （CRAC） channels, the molecular mechanism of channel gating by the CRAC channel activator, stromal interaction molecule 1 （STIM1）, remains unknown. CRAC channels are distinguished by a very high Ca2+ selectivity and are instrumental in generating sustained intracellular calcium concentration elevations that are necessary for gene expression and effector function in many eukaryotic cells2. Here we probe the central features of the STIM1 gating mechanism in the human CRAC channel protein, ORAI1, and identify V102, a residue located in the extracellular region of the pore, as a candidate for the channel gate. Mutations at V102 produce constitutively active CRAC channels that are open even in the absence of STIM1. Unexpectedly, although STIM1-free V102 mutant channels are not Ca2+-selective, their Ca2+ selectivity is dose-dependently boosted by interactions with STIM1. Similar enhancement of Ca2+ selectivity is also seen in wild-type ORAI1 channels by increasing the number of STIM1 activation domains that are directly tethered to ORAI1 channels, or by increasing the relative expression of full-length STIM1. Thus, exquisite Ca2+ selectivity is not an intrinsic property of CRAC channels but rather a tuneable feature that is bestowed on otherwise non-selective ORAI1 channels by STIM1. Our results demonstrate that STIM1-mediated gating of CRAC channels occurs through an unusual mechanism in which permeation and gating are closely coupled.